Background The human gut microbiota produces short-chain carboxylic acids (SCCA) through fermentation of undigested carbohydrates, and through chain elongation, a process that can be modulated through diet. Valerate is frequently recovered from human fecal samples, but little is known about dietary components, microbial contributors, and cross-feeding interactions that drive human intestinal valerate formation. We combined co-culture studies and in vitro human fecal microbiota batch fermentations (n = 20) with the analysis of a free-living cohort of obese and overweight women (n = 49) that monitored and modified (fermented) dairy consumption, to study the role of dairy-derived lactose and lactate in intestinal microbial formation of valerate. Results While the valerate producer Megasphaera elsdenii was not able to use lactose in single culture, valerate was formed (6.2 ± 1.3 mM) in co-culture with the lactose-utilizing and lactate-producing food microbe Streptococcus thermophilus. In vitro, valerate was produced by fecal microbiota of most donors (15/20) in control medium. Lactose addition significantly (p < 0.05) increased valerate formation of fecal microbiota that harbored Megasphaera at levels ≥ 5 log cells/mL (n = 4), while valerate formation was lower when Megasphaera was less abundant or not detected (n = 15). The addition of M. elsdenii to batch fermentations increased valerate production in 80% of samples and correlation analysis showed a positive correlation (p < 0.001) between relative abundance of Megasphaera and valerate levels. In vivo, 30% of study participants harbored Megasphaera based on 16S rRNA gene amplicon sequencing and species-specific qPCR. Diet supplementation with drained yogurt (skyr) led to higher fecal microbial diversity (p < 0.05) and relative abundance of Streptococcaceae. Participants that harbored Megasphaera and consumed skyr daily had significantly (p < 0.05) higher fecal valerate levels at week 6 compared to controls. In addition, fecal levels of lactate were higher in the skyr compared to the control group at 12 weeks. Linear discriminant analysis suggested co-occurrence of Megasphaera with the lactate-producer Lactobacillus and competition with other lactate utilizers such as the Anaerobutyricum hallii group. Conclusion This study brings forward new mechanistic understanding on the intestinal microbial formation of the SCCA valerate. Our findings identified Megasphaera as an infrequently occurring and low abundant keystone taxon contributing to lactose/lactate-driven valerate production in overweight/obese women. Our results highlight that the presence of Megasphaera affects the fermentative response to daily consumption of fermented dairy. <MediaObject ID="MOESM3"> <VideoObject FileRef="MediaObjects/40168_2025_2207_MOESM3_ESM.mp4" VideoID="-KKQdUm6UBh7B9pv1VSaWe"> <Caption Language="En" xml:lang="en"> <CaptionContent> Video Abstract </CaptionContent> </Caption> </VideoObject> </MediaObject>

Megasphaera contributes to lactate-driven valerate production in the human gut

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2025年10月21日

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Lucía Huertas-Díaz,
Mensure Elvan Gezer,
Angeliki Marietou,
Jiri Hosek,
Line Thams,
Line Barner Dalgaard,
Mette Hansen,
Clarissa Schwab

摘要

Background

The human gut microbiota produces short-chain carboxylic acids (SCCA) through fermentation of undigested carbohydrates, and through chain elongation, a process that can be modulated through diet. Valerate is frequently recovered from human fecal samples, but little is known about dietary components, microbial contributors, and cross-feeding interactions that drive human intestinal valerate formation. We combined co-culture studies and in vitro human fecal microbiota batch fermentations (n = 20) with the analysis of a free-living cohort of obese and overweight women (n = 49) that monitored and modified (fermented) dairy consumption, to study the role of dairy-derived lactose and lactate in intestinal microbial formation of valerate.

Results

While the valerate producer Megasphaera elsdenii was not able to use lactose in single culture, valerate was formed (6.2 ± 1.3 mM) in co-culture with the lactose-utilizing and lactate-producing food microbe Streptococcus thermophilus. In vitro, valerate was produced by fecal microbiota of most donors (15/20) in control medium. Lactose addition significantly (p < 0.05) increased valerate formation of fecal microbiota that harbored Megasphaera at levels ≥ 5 log cells/mL (n = 4), while valerate formation was lower when Megasphaera was less abundant or not detected (n = 15). The addition of M. elsdenii to batch fermentations increased valerate production in 80% of samples and correlation analysis showed a positive correlation (p < 0.001) between relative abundance of Megasphaera and valerate levels. In vivo, 30% of study participants harbored Megasphaera based on 16S rRNA gene amplicon sequencing and species-specific qPCR. Diet supplementation with drained yogurt (skyr) led to higher fecal microbial diversity (p < 0.05) and relative abundance of Streptococcaceae. Participants that harbored Megasphaera and consumed skyr daily had significantly (p < 0.05) higher fecal valerate levels at week 6 compared to controls. In addition, fecal levels of lactate were higher in the skyr compared to the control group at 12 weeks. Linear discriminant analysis suggested co-occurrence of Megasphaera with the lactate-producer Lactobacillus and competition with other lactate utilizers such as the Anaerobutyricum hallii group.

Conclusion

This study brings forward new mechanistic understanding on the intestinal microbial formation of the SCCA valerate. Our findings identified Megasphaera as an infrequently occurring and low abundant keystone taxon contributing to lactose/lactate-driven valerate production in overweight/obese women. Our results highlight that the presence of Megasphaera affects the fermentative response to daily consumption of fermented dairy.

Video Abstract